6alpha-fluoro-16alpha-methyl derivatives of the pregnane series



United States Patent 0 1 3,499,016 6a-FLUORO-16a-METHYL DERIVATIVES OFTHE PREGNANE SERIES Frank H. Lincoln, William P. Schneider, George B.Spero,

Kalamazoo, Mich., assignors to The Upjohn Company,

Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed Aug. 4,1958, Ser. No. 753,157

Int. Cl. C07c 169/30, 169/34; A61k 17/06 U.S. Cl. 260397.45 30 ClaimsThis invention relates to certain novel steroids, more particularly to6:1 fiuoro 11fl,170c,21 trihydroxy-16a- 3,499,016 Patented Mar. 3, 197010 formulae:

(F0 OR $00K CH CH H3O H30 11 OH HaC (I'JOOR emu-o fin-o n CH the n O"CH; 0' i CH: 3 HaC i I J (are 0 l l 5 1v 111-0 5 I III F R 5" on 200R(IJHr-OH OH on mo H 11,0 0 "OH; HO/\' on, H20 H20 I R! R! I clam-o emu-0l CHO v CHO/ v1 1'1 5 t It a l on on CH2OAc CH2-OA0 H H3O E30 H ---OHHoon. E0 "on, H39 H10 I l I (oH)n-o (omu-o CHO VIII CH-O v11 1'1 i It awherein R is lower-alkyl, i.e., containing from one to eight carbonatoms, inclusive, preferably methyl or ethyl, 70 R is hydrogen orlower-alkyl, preferably hydrogen, R"

is an aryl or alkyl sulfonyl radical preferably that of a hydrocarbonsulfonic acid containing from one to twelve carbon atoms, inclusive,e.g., lower-alkyl, methyl, aryl, phenyl, p-tolyl, sym.-xylyl-sulfonicacid, n is an integer 7 from one to two. A0 is the acyl radical of ahydrocarbon carboxylic acid containing from one to twelve carbon atoms,inclusive, X is a halogen having an atomic weight from 35 to 127,inclusive, i.e., chlorine, bromine or iodine, X is a halogen having anatomic weight from nineteen to 127, inclusive, i.e., fluorine, chlorine,bromine or iodine, and X" is hydrogen, fluorine or chlorine. Loweralkyl,wherever it appears means containing from one to eight carbon atoms,inclusive, e.g., methyl, ethyl, propyl, octyl. The dotted line appearingin Formulae XI to XXIV represents a h -double bond which may or may notbe present, i.e., the formulae represent both the A and A compounds.

It is an object of this invention to provide the novel6a-fluor0-11B,17ot,21 trihydroxy 161x methyl-4-pregnene-3,20dione and21-esters thereof, 6a,9a-difluoro-11fi,17a,2l-trihydroxy-16a-methyl-4-pregnene 3,20 dione, esters thereof andthe 9a-bromo, 9a-iodo and 9a-chloro analogues thereof that areintermediates in the production of the 9a-fluoro compound, as well asthe 9(1l)-dehydro and 95,11B-epxy intermediates in the production of the9a'-fluoro compound, 6ot-fll10lO-l6ot-H16ihYl-170:,21-dihydroxy-4-pregnene-3,11,20-trione and 21-esters thereof,6a,9otdifiuoro-l6a-methyl-17x,21-dihydroxy 4 pregnene-3,11,20-trione and21-esters thereof, as well as the 9a-chloro, 9a-bromo and 9OL-lOdOanalogues thereof, 60:- fl110IO-1L8,l7oc dihydroxy16a-methyl-4-pregnene-3,20- dione, 6a-fll1OI'O-9a-Chl0r0- and60!,9w-dlfl1lOIO-11 {3,17a-dihydroxy-l6ot methyl 4 pregnene-3,20-dioneand intermediates in the production thereof, 6m-fluoro-16a-methyl- 170ahydroxy 4 pregnene-3,11,20-trione, 6a-fluoro-9achloroand 60,9OLdifluoro-16a-methyl17u-dihydroxy-4- pregnene-3,1l,20-trione, 60,21difluoro 11/3,17a-dihydroxy-16a-methyl'4-pregnene-3,20-dione, 6a,21difluoro- 9a-Chl0l'0- and6a,9a,21-trifluoro-11f3,17a-dihydroxy-16amethyl-4-pregnene-3,20-dione,and intermediates in the production thereof, 60,21-dlfi110fO-l6ot methyl170L-hydroxy 4 preguene-3,l1,20-trione, 6a,2l difluoro 90cchloroand6u,9a,2l trifiuoro 16a-methyl-l7a-hydroxy- 4-pregnene-3,11,20-trione andintermediates in the production of the above compounds, and the o-analogues of each of the above compounds It is another object toprovide processes for the production thereof and pharma ceuticalpreparations and mixtures thereof. Other objects will be apparent tothose skilled in the art to which this invention pertains.

The novel compounds of this invention, especially60cfluoro-llfl,l7a,21-trihydroxy 16a methyl 4 pregnene- 3,20-dione,fia-fiuoro 16a. methyl-170:2l-dihydroxy-ftpregnene-3,11,20-trione,6a-fluoro 1l}3,17oc,21 trihydroxy-l6a-methyl 1,4 pregnadiene-3,20-dione,6a-fiu- 0ro-16a-methyl 17,21 dihydroxy-1,4-pregnadiene-3, 11,20-trione,6a,9a-difil10rO-11fi,l7oc,2l trihydroxy 16amethyl-4-pregnene 3,20 dione,6a,9a difluoro 16amethyl-l701,21-dihydroxy-4-pregnene-3,11,20 trione,6oz, 9a-difluoro-11fl,17a21 trihydroxy16a-methyl-1,4-pregnadiene-3,20-dione, 6a,9a difluoro160t-Il'1ethy1-17OL,21- dihydroxy-1,4-pregnadiene-3,1l,20-trione andtheir 21- esters as defined hereinabove, and the 21-desoxy-21-fluoro and21-desoxy analogues thereof, are highly active antiinflammatory agentswith improved ratio of therapeutic activity to undesirable side-effects,e.g., gastrointestinal disturbances, salt retention, edema, etc., knownto exist with similar known physiologically active steroids. Many of thehigher molecular weight esters, particularly the ones resistant tohydrolysis and/or more insoluble in body fluids, provide compounds withprolonged activity over the corresponding 21-hydroxy compounds. Thecompounds named above are useful in the treatment of variousinflammatory conditions of the skin, eyes, respiratory tract and thebones and internal organs due to bacterial or viral infections, contactdermatitis and allergic reactions, rheumatoid arthritis, and possessimproved therapeutic ratios of anti-inflammatory activity to undesirableside-effects, compared to the corresponding compounds without the methylgroup. For this purpose they may be incorporated in the various inertointments, cremes, lotions and sprays well known in the art They may becombined with the known antibiotics, especially the penicillins,neomycin, tetracycline, chloromycetin and novobiocin. The 9a-chlorocompounds of the present invention, While somewhat less active asanti-inflammatory agents than the corresponding 9ot-fluoro compounds,often have a better therapeutic ratio of anti-inflammatory activity toundesirable side-effects, e.g., catabolic activity.

Other of the compounds of the present invention, as well as being usefulas intermediates in the production of the above-described compounds alsopossess useful physiological activity, including glucocorticoid,mineralocorticoid and anti-inflammatory activity. Notable among thesecompounds XIII, XIV and XV, and the corresponding 21- hydroxy compounds.

The novel compounds of the present invention are prepared from3,11-diketo-16a-methy1-4J7(20)-[cis]-pregnadien-Zl-oic acid lower-alkylester (I) by the following reactions: The 3-keto group is ketalizedaccording to the method of US. Patent 2,707,184 or 2,758,993 to producethe 3-ketal of 3,11-diketol'6ot-methyl-4,17(20)-[cis]-pregnadien-21-oicacid lower-alkyl ester (II). Ethylene glycol is the preferred ketalizingagent and the methyl and ethyl esters are preferred.

The next step of the process of this invention involves the epoxidationof the 5 (6)-double bond of 3-ketal of 3,11 diketo 16a methyl 4,17(20)[cis] pregnadien-Zl-oic acid lower-alkyl ester with a peracid, e.g.,peracetic or perbenzoic, or other known epoxidizing agents, to producethe corresponding 5,6-epoxide (III). A mixture of both the aandfl-epoxides is produced in this epoxidation reaction, and the mixturecan be separated by chromatographic or crystallization techniques knownin the art. The a-epoxide is employed in the next ste The next step isan epoxide opening step in which a 3 ketalized 3,11 diketo 5ot,6oc epoxy16a methyl- 17(20) [cis] allopregnen 21 oil acid lower-alkyl ester(III). is reacted with hydrogen fluoride, to open the oxide ring andproduce the corresponding S-ketalized 3,11- diketo 50c hydroxy 66 fluoro16a methyl 17(20)- [cis]-allopregnen-21-oic acid lower-alkyl ester (V).This epoxide opening step is ordinarily carried out at temperaturesbetween about minus forty and plus fifty degrees centigrade, thepreferred limits being between about zero and 25 degrees centigrade. Itcan be performed under anhydrous conditions in the presence or absenceof a catalyst, e.g., boron trifluoride, or under aqueous conditions inwhich case the ketal group is removed by hydrolysis. Reactionconditions, e.g., those disclosed by Schmidlin et al., Helv. Chim. Acta,36, 1241 (1953); Gallagher, J. Biol, Chem., 162, 495 (1946); Cornforthet al., J. Chem. 800., 1954, 907 and Fried et al., I. Am. Chem. Soc, 75,2273 (1953), are usually employed. As anhydrous conditions are oftendiflicult or inconvenient to maintain, the oxide opening reaction ispreferably performed under aqueous conditions in which case the ketalgroup will be hydrolyzed at the same time to produce IV. Thethus-produced 3-keto group of IV can then be reketalized in the mannerdescribed hereinabove to produce the corresponding ketal (V).

The next step of the process of the present invention is a reductionstep in which a 3-ketalized 3keto-5ot-hydroxy 65 fluoro 16cc methyl17(20) [cis] allopregnen-Zl-oic acid lower-alkyl ester (V), preferablythe 3-ethylene glycol ketal of 3,11-diketo-5a-hydroxy-6flfluoro 16ccmethyl 17(20) [cis] allopregnen 21- oic acid lower-alkyl, preferablymethyl or ethyl, ester, is reduced with lithium aluminum hydride orother chemical carboxyl reducing agent in an organic solvent, e.g.,ether, dioxane, tetrahydrofuran, benzene, to produce the corresponding3-ketalized 50:,1 1 8,21-trihydroxy-6 3-fluoro-16ot-methyl-17(20)-[cis]-allopregnen-3-one. At completion of thisreaction, the reaction mixture is preferably mixed with water or, anacid, an ester or carbonyl agent followed by water, to decompose anyexcess lithium aluminum hydride and organo-metal complexes. The usualreaction conditions for a lithium aluminum hydride reduction areemployed, except that a reaction temperature at room temperature orbelow is preferred, and

acid, though operative and satisfactory under carefully controlledconditions, is preferably not employed in the decomposition step, toavoid undue hydrolysis of the ketal group.

The next step is an esterification reaction involving the conversion ofthe 21-hydroxy group of a 3-ketal of 5a,l1cz,2l trihydroxy 6,3 fluoro16a methyl l7 (20)-[cis]-allopregnen-3-one (VI) to a 21-acyloxy group soas to protect the 21-hydroxy group in the next step, i.e., the oxidativehydroxylation step. This reaction can be performed under theesterification conditions known in the art, e.g., by the reaction of IVwith the selected acid halide or acid chloride or acid bromide or theanhydride of a hydrocarbon carboxylic acid, or by reaction with theselected acid, in the presence of an esterification catalyst or with anester under ester exchange reaction conditions. Reaction conditionswhich are apt to alfect the labile S-ketal group, the H S-hydroxy groupor the 6-fluoro group should be avoided.

In the next step of the process of this invention, the thus-producedester (VIII) is then oxidatively hydroxylated with osmium tetroxide andan oxidizing reagent, e.g., hydrogen peroxide, organic, organic peracid,an amine oxide peroxide, or an aryl iodo oxide, in the manner describedin US. Patents 2,769,825, 2,769,823 or in Hogg et al., J. Am. Chem.Soc., 77, 4436 (1955), to produce the corresponding 3-ketal of 5a,113,17a,21-tetrahydroxy 6B fluoro 16a methylallopregnane 3,20- dione21-acylate (VIH).

The next step of the process of this invention involves the simulatneousremoval of the 3-ketal group, the dehydration of the Sat-hydroxy groupand the epimerization of the 6,6-fluoro group of a 3-ketal of5a,11;3,17a,21-tetrahydroxy -65 fluoro 16cc methylallopregnane 3,20-dione 21-acylate to produce 6a-fluoro-11 3,17a,21-trihydroxy 16oz methyl4 pregnene 3,20 dione 21-acylate (IX). Although these reactions can beperformed in sequence, i.e., removal of the 3-ketal under mildly acidicconditions, the dehydration using Girards Reagent T and theepimerization using anhydrous mineral acid, these reactions arepreferably performed simultaneously. This can be accomplished underacidic conditions, preferably employing a mineral acid in alower-alkanol, preferably methanol or ethanol, and an inert solvent forthe steroid, e.g., chloroform or methylene chloride.

The starting 3,11 diketo 16oz methyl-4,l7(20)-[cis]- pregnadien-Zl-oicacid methyl ester is prepared from the knownll-keto-16-dehydroprogesterone by the following reactions: The 3-ketogroup of 11-keto-16-dehydroprogesterone is selectively protected fromreaction by conversion to a 3-enamine, e.g., pyrrolidyl enamine,according to procedures well known in the art. The 3-enamine of 11-keto-l-dehydroprogesterone is then reacted with a methyl Grignardreagent, preferably methyl magnesium bromide or iodide, in the presenceof a 1,4-addition promoting reagent, e.g., cuprous chloride, [SeeGrignard Reactions, Kharasch and Reinmuth, Prentice Hall, Inc.Publishers (1954), page 219, for a discussion of other catalysts], toproduce the 3-enamine of 1l-keto-16a-methylprogesterone. The 3-enarninegroup is then hydrolyzed, e.g., with aqueous alkali to produce11-keto-16u-methylprogesterone.

1l-keto-16a-methylprogesterone is then converted to 3,11 diketo 16amethyl 4,l7(20) [cis] pregnadien- 2l-oic acid lower-alkyl ester (I) inthe manner described in US. Patent 2,790,814 for the conversion ofll-ketoprogesterone to 3,11-diketo-4,17(20)-pregnadien-21-oic acidmethyl ester, i.e., 1l-keto-l6u-methylprogesterone is reacted with morethan two molar equivalents each of an alkyl diester of oxalic acid,preferably methyl or ethyl oxalate, and a base, preferably sodiummethoxide or ethoxide or potassium tertiary butoxide, to produce thealkali-metal dienolate of2,21-dialkoxyoxalyl-11-keto-16amethylprogesterone. This compound, or thefree enol, e.g., prepared by reaction of the alkali-metal dienolate withacetic acid, is then trihalogenated with chlorine or bromine, preferablythe latter, to produce 2,21-dialkoxyoxalyl 2,21,21trihalo-ll-keto-16a-methylprogesterone. This compound rearranges withstrong base, e.g., an alkali-metal alkoxide, in the presence of analkanol, e.g., sodium methoxide or ethoxide in methanol or ethanol, toproduce 2 halo 3,1l-diketo-l6a-methyl-4,17(20)-[cis]- pregnadien-Zl-oicacid alkyl ester. The 2-halo group is removed by zinc and acetic acid orother halogen removing agent to produce3,1l-diketo-l6a-methyl-4,17(20)-[cis]- pregnadien-Zl-oic acid alkylester (I).

60: fluoro 1118,17a,21 trihydroxy 16oz methyl 4- pregnene-3,20-dione(IX) or its 21-acylate (IX) preferably the 21-acetate, can be convertedto numerous physiologically active steroids. For example, it can bedehydrogenated in the one position with selenium dioxide or a funguscapable of dehydrogenating at the one position without otherwisedegrading the nucleus, e.g., of the genus Septornyxa, to produce6a-fluoro-11/8,17a,21-trihydroxy- 16u-rnethyl-1,4-pregnadiene-3,20-dione(X). This compound, in turn, can be esterified to produce its 2l-esters(X') according to methods known in the art.

61x fluoro 11fl,17a,21 trihydroxy 16oz methyl 4- pregnene-3,20-dione21-acylate (IX) and 6oz-flu0rO-l1/3, 170;,21 trihydroxy 16oz methyl 1,4pregnadiene-3,20- dione ZI-acylate (X'), represented collectively byFormula XI, can be oxidized with a N-haloamide or N- haloimide, e.g.,N-bromoacetamide in pyridine or like amine, or with chromic acid orsodium dichromate, according to methods known in the art, to produce thecorresponding ll-keto compounds (XII) which, in turn, can be hydrolyzedin the manner described herein to produce the corresponding 21-hydroxycompounds.

The 6oz,9a-dihal0 compounds of the present invention are prepared asfollows: dehydrating a 6a-fluoro-11 3,l7a, 21 trihydroxy 16cc methyl 1,4pregnadiene 3,20- dione 21-acylate or a 6a-fluoro-1113,17a,21-trihydroxy-16amethyl-4-pregnene-3,20-dione 21-acylate (XI),illustratively with sulfuric acid or preferably with an N-haloamidefollowed by anhydrous sulfur dioxide, produces the corresponding 6afluoro 16oz methyl 170:,21 dihydroxy- 1,4,9(11) pregnatriene 3,20 dione21 acylate and 6afiuoro 16oz methyl 1704,21 dihydroxy 4,9(11)pregnadiene-3,20-dione 21-acylate, respectively (XIII). Addition of ahypohalous acid, i.e., hypochlorous, hypoiodous or hypobromous acid, tothese latter compounds produces the corresponding 60c fluoro 9a halo11;3,17a,21 trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 21 acylateand 6a fluoro 9oz halo-1 113,170:,2l-tfil1Ydl'0XY-16umethyl 4 pregnene3,20 dione 21-acylate, respectively (XIV), which by treatment with abase, e.g., anhydrous potassium acetate, yields the corresponding epoxycompounds (XV), i.e., 6a-fluoro-9B,11fl-epoxy-16or-methyl-17a,21-dihydroxy-1,4-pregnadiene 3,20 dione 21-acylate and 6a-flu0ro-9fi, 1 1B-epoxy-16a-methyl-Hull-dihydroxy-4-pregnene-3,20-dione 21-acylate, respectively. Treatment of these epoxycompounds with hydrogen fluoride or other hydrogen fluoride releasingagents produces the highly active6u,9u-difluoro-l1B,17a,21-trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 21-acylate and 6a,9a-difluoro-11l3, 1711,21trihydroxy-16a-methyl-4-pregnene-3,ZO-dione 21- acylate, respectively(XVI). Oxidation of these latter compounds, preferably the 21-acetate,with chromic acid in acetic acid provides6a,9u-difluoro-16a-methy1-17a,21-dihydroxy-1,4-pregnadiene-3,11,20-trione2l-acylate and 6a, 9a difluoro 16a methyl 1704,21 dihydroxy 4pregnene-3,11,20-trione 21-acylate, respectively (XVH). Hydrolysis ofthe esters XVII with a base, e.g., aqueous sodium hydroxide or sodiumbicarbonate, provides the free alcohols6a,9a-difluoro-16a-methyl-17a,2l-dihydroxy-1,4-pregnadiene-3,l1,20-trione and 6a,9a difluoro cmethyl :,21 dihydroxy4 pregnene 3,11,20-trione. The esters of XVI are similarly hydrolyzed tothe corresponding 2l-hydroxy compounds.

The 6a,2l-difluoro compounds of the present invention are prepared bytreating Ga-fluoro-llB,17u,2I-trihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione and 6a-fiuoro-11,8,17m,21-trihydroxy-16a-methyl-4-pregnene-3,20-dione, respectively,(XVIII) or the corresponding ll-keto compounds or their 9a-chloro or9a-fiuoro analogues with an organic sulfonyl halide such asmethanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonylbromide, benzenesulfonyl chloride, naphthylenesulfonyl chloride, or thelike, to obtain the corresponding 21-sulfonate ester (XIX), e. g.,6u-fluoro-l 1 p, 17 a,2l-tlihYdrOXY-l6a-II16II1Y1- 4-pregnene-3,20-dioneZI-methylsulfonate or 21-p-t0luenesulfonate or their 90t-ChlOI'O or9a-fluoro analogues; treating the thus-produced 21-alkyl or arylsulfonate with sodium iodide in acetone solution to obtain thecorresponding 21-iodo compounds (XXII), e.g.,6a-fiUO1'O-llfi,17oc-dlhydroxy16a-methyl-21-iodo-1,4-pregnadiene-3,20-dione and 60afluoro-l16,17a-dihydrxy-l6a-methyl-21-iodo-4- pregnene-3,20-dione ortheir 9a-fiuoro or 9OL-Chl0l'0 analogues; treating the thus-obtained21-iodo compounds with silver fluoride, preferably in acetonitrilesolution to obtain the corresponding 21-fiuoro compound (XX), e.g.,6u,21 difluoro l1B,l7a-dihydroxy-l6a-methyl-1,4-pregnadiene-3,20-dioneand 60:,2l-difil10IO-l lfl,l7u-dihydroxy-16a-methyl-4-pregnene-3,20-dione or their 9a-fiuoro or 90:- chloroanalogues; and if desired oxidizing the thus-obtained 21-fiuorocompounds with chromic anhydride, N- bromoacetamide, N-bromosuccinimide,or the like, to give the corresponding ll-keto compounds (XXI), e.g.,6u,21-

difluoro-16u-methyl-17a-hydroxy-1,4- pregnadiene-3,1 1,20-

trione' and6u,2l-difiuoro-l6a-methyl-17a-hydroxy-4-pregnene-3,11,20-trione or their9oc-flUOI'O or 9a-chloro analogues. Alternatively, the 21-sulfonate,preferably the 21-methylsulfonate, can be treated directly withpotassium fluoride in dimethyl sulfoxide, e.g., at 100 degrees foreighteen hours or longer, to produce the 6a,21-difluoro compoundsdirectly. The corresponding ll-keto analogues of these compounds,prepared by oxidizing the llfl-hydroxy group of a compound representedby Formula XIX, are similarly converted from their 21-su1fonate esterdirectly to the 21-fluoro compounds.

The 21-unsubstituted compounds of the present invention (XXIII, XIV),are prepared by treating a 21-iodo compound (XXII), e.g.,6a-fiuoro-115,17a-dihydroxy-16amethyl-Zl-iodo-1,4-pregnadiene-3,ZO-dioneand Gut-fluoro- 115,170: dihydroxy-l6a-methyl-21-iodo-4-pregnene-3,20-dione, with a reducing agent such as sodium thiosulfate, sodiumbisulfite, potassium bisulfite, or the like, in an aqueous organicsolvent mixture, to obtain the corresponding 21-unsubstituted compound(XXIII) and if desired oxidizing the thus-obtained 21-unsubstitutedcompound with chromic anhydride, N-bromoacetamide, N- bromosuccinimide,or the like, to give the corresponding ll-keto compound (XXIV), e.g.,6u-fiuoro-16a-methyl- 17a-hydroxy-1,4-pregnadiene-3,11,20-trione and6a-fluoro- 16a-methyl-17u-hydroxy-4-pregnene-3,l1,20 trione. The90c-Chl010 and 9a-fluoro-2l-unsubstituted compounds (XXIII, XXIV, X=Cl,F) are prepared by substituting the corresponding 9m-halo-21-iodocompounds (XXII, X=Cl, F) as starting compounds in the above-describedreaction or converting the 9-hydrogen compounds to 90- chloro and9u-fluoro compounds via the 9(1l)-'dehydro compound in the mannerdescribed hereinbefore.

The following preparations and examples are illustrative of the productsand processes of this invention, but

are not to be construed as limiting.

PREPARATION 1 1 1 -keto-I 6 a-methylprogesterone To a hot solution of4.56 grams (0.014 mole) of 11- keto-l6-dehydroprogesterone in 45milliliters of methanol was added 2.25 milliliters of pyrrolidine withswirling. The reaction product, the 3-pyrrolidyl enamine or 11-keto-16-dehydroprogesterone, soon separated as yellowish crystals. Aftercooling to five degrees, the mixture was 12 filtered, the cake washedwith cold methanol and dried under vacuum. There was obtained 4.56 gramsof 3- pyrrolidyl-3,5,16-pregnatriene-11,20-dione melting at 154 to 169degrees Centigrade.

A solution of the thus-obtained enamine in milliliters oftetrahydrofuran was added slowly to a stirred suspension of 45milliliters of commercial three molar methyl magnesium bromide, 0.90gram of cuprous chloride and fifty milliliters of tetrahydrofuran. Themixture was cooled to room temperature and stirred under a nitrogenatmosphere for three hours. The excess Grignard reagent was cautiouslydestroyed by the dropwise addition of 6.5 milliliters of water. To themixture, containing 3-pyrrolidyl-16a-methyl-3,5-pregnadiene-l1,20-dione,was added four milliliters of acetic acid and sixteen milliliters ofmethanol and the mixture was warmed until a clear dark yellow solutionwas obtained. Sixteen milliliters of a ten percent aqueous solution ofsodium hydroxide was added, bringing the pH to 8. The mixture was heatedunder reflux for 45 minutes. One milliliter of acetic acid and 250milliliters of water were added and the cooled mixture was extractedthree times with methylene chloride. The combined extracts were washedwith an aqueous sodium bicarbonate solution, water and then dried withsodium sulfate. The dried solution was evaporated and the residue,consisting essentially of 1l-keto-16a-methylprogesterone, was dissolvedin 400 milliliters of methylene chloride and chromatographed through aZOO-gram column of magnesium silicate (Florisil). The column wasdeveloped with 400-milliliter portions of solvent of the followingcomposition and order: five of hexanes (Skellysolve B) plus threepercent acetone, five of hexanes plus five percent acetone, eight ofhexanes plus seven percent acetone, five of hexanes plus ten percentacetone, four of hexanes plus fifteen percent acetone and finally, oneof acetone. Fractions 9 to 25 (counting the methylene chloride fraction)were combined and recrystallized from a mixture of acetone and water togive 2.03 grams of 11- keto-16a-methylprogesterone melting at 179 to 182degrees centigrade. A sample recrystallized from a mixture of ethylacetate and hexanes melted at 183 to 185 degrees centigrade, had an [0:]of plus 255 degrees (CHCI a 15,850 and the analysis below.

Analysis.Calculated for C H O C, 77.15; H, 8.83. Found: C, 76.95; H,8.98.

PREPARATION 2 A solution of 2.00 grams (5.8 millimoles) of 11-keto-16a-methylprogesterone in thirty milliliters of dry tertiary butylalcohol was warmed to fifty degrees centigrade and stirred undernitrogen. To the solution was added 3.2 milliliters of ethyl oxalate and3.03 grams of a 25 percent methanolic sodium methoxide solution. Ayellow-green precipitate of the sodium dienolate of 2,21-diethoxyoxalyl-1l-keto-lfia-methylprogesterone appeared almost immediately.

The mixture was stirred for twenty minutes after which a cooled solutionof 0.98 gram of anhydrous sodium acetate and 0.84 milliliter of aceticacid in forty milliliters of methanol was added, thus producing the freedienol. The solution was cooled to zero degrees centigrade and thentreated dropwise with a cold solution of 2.0 grams of bromine inmethanol over a period of ten minutes. There was thus-produced 2,21,21tribromo 2,21 diethoxyoxalyl- 1 l-keto- 1 6a-methylprogesterone.

The cooling bath was removed and to the solution was added 5.72 grams ofa 25 percent methanolic sodium methoxide solution. The stirring wascontinued for 2.5 hours. There was thus produced2-bromo-3,l1-diketo-16amethyl-4,17(20)-[cis] -pregnadien-21-oic acidmethyl ester.

To the resulting solution was then added five milliliters of acetic acidand one gram of zinc dust and stirring was continued for thirty minutes.The mixture was diluted with water, the solids were removed byfiltration, and the filtrate extracted thoroughly with methylenechloride. The extract was dried with sodium sulfate and evaporated. Theresidue was dissolved in 400 milliliters of methylene chloride andpoured over a 200-gram column of magnesium silicate (Florisil). Thecolumn was developed with 400- milliliter portions of solvent of thefollowing composition and order: four of hexanes (Skellysolve B) plusfive percent acetone, ten of hexanes plus seven percent acetone, ten ofhexanes plus ten percent acetone and finally, one of acetone. Fractions14 to 23 (counting the methylene chloride fraction) contained starting11-keto-16a-methylprogesterone. Fraction 7 to 12 contained3,11-diketo-l6mmethyl-4,17(20)-[cis]-pregnadien-2l-oic acid methyl esterwhich, when crystallized from methanol and Water and then from methanol,melted at 177 to 184 degrees centigrade, has a a 26,200, an [111 of plus137 degrees (CHCl and the analysis below.

Analysis.Calculated for C l-1 C, 74.56; H, 8.16. Found: C, 74.58; H,8.04.

The yield of product is increased if the initial reaction of1l-keto-la-methylprogesterone with ethyl oxalate and sodium methoxide isconducted at somewhat higher temperatures and/ or with longer reactiontimes.

EXAMPLE 1 The 3-ethylene glycol ketal of 3,11-diket0-16a-methyl- 4,17()-[cis]-pregnadien-21-0ic acid methyl ester To a solution of 1.5 gramsof 3,11-diketo-16d-methyl- 4,17(20)-[cis]-pregnadien-Zl-oic acid methylester dissolved in 150 milliliters of benzene was added 7.5 millilitersof ethylene glycol and 0.150 gram of para-toluenesulfonic acid and thewhole was then heated with stirring at the reflux temperature of thereaction mixture for 5.5 hours. The water formed in the reaction wasremoved by passing the condensate through a water trap. The cooledreaction mixture was washed with 100 milliliters of a one percentaqueous sodium bicarbonate solution. The benzene layer was then pouredon a column of 150 grams of magnesium silicate (Florisil). The columnwas developed with 100-milliliter portions of solvent of the followingcomposition and order: eight portions of methylene chloride plus fourpercent acetone and three portions of methylene chloride plus eightpercent acetone. The methylene chloride plus four percent acetoneeluates contained the 3-ethylene glycol ketal of 3,11-diketo-16u-methyl4,17(20) [cis] pregnadien 21 oic acid methyl ester which was freed ofsolvent by evaporation.

Reacting 3,11 diketo 16cc methyl 4,17(20 [cis]- pregnadien-2l-oic acidmethyl ester with tn'methylene glycol in the presence ofpara-toluenesulfonic acid is productive of the S-trimethylene glycolketal of 3,11-dik610-l6amethyl-4,17'(20)-[cis]-pregnadien-Zl-cic acidmethyl ester.

Similarly, other 3-ketals of this and other esters of 3,11- diketo 16ozmethyl 4,17(20) [cis] pregnadien 21- oic acid methyl ester are producedby the reaction of the selected ester of 3,11 diketo 16m methyl4,17(20)- [cis]-pregnadien-Zl-oic acid, e.g., methyl, ethyl, propyl,butyl, or octyl ester, with a glycol as hereinbefore described, e.g.,ethylene glycol, propylene glycol, trimethylene glycol, lower-alkylsubstituted ethylene glycols or trimethylene glycols, in the presence ofan acid catalyst, e.g., para-toluenesulfonic acid, hydrogen chloride,sulfuric acid.

EXAMPLE 2 3-ethylene-glyc0l ketal 0f3,11-diket0-5u,6a-ep0xy-16amethyl-17(20)-[cis]-pregnen-21-0ic acidmethyl ester To a solution of five grams of the 3-ethylene glycol ketalof 3,11 diketo 16a methyl 4,17(20) [cis]- pregnadien-Zl-oic acid methylester in milliliters of chloroform was added a chilled solution of 1.9grams of perbenzoic acid dissolved in 31.5 milliliters of chloroform.The solution was maintained at about four degrees centigrade for 24hours, and then at room temperature for 72 hours. The solution was thenwashed with a five percent aqueous solution of sodium bicarbonate andthen with water. The chloroform layer was separated, dried and thesolvent distilled to give a residue of the S-ethylene glycol ketal of3,11 diketo 5a,6a epoxy 16a methyl-17(20)-[cis]-pregnen-2l-oic acidmethyl ester.

EXAMPLE 3 3,11 diketo 50c hydroxy-6fl-flu0ro-16a-methyl-17(20)-allopregnen-ZZ-oic acid methyl ester To a solution of 1.73 grams of3-ethylene glycol ketal of 3,11 diketo5oz,6oc-ep0Xy-16a-methYl-17(20)-[CiS]- pregnen-Zl-oic acid methyl esterin sixteen milliliters of methylene chloride was added six millilitersof 48 percent hydrofluoric acid. The heterogeneous mixture was stirredfor two hours, made slightly basic with 300 milliliters of five percentsodium bicarbonate solution, and extracted with methylene chloride. Theextract was washed, dried, and evaporated to dryness to give 1.62 gramsof crude solid. Purification by chromatography over magnesium silicategave two fractions. The first was eluted with methylene chloride plusfive percent acetone and the second was eluted with methylene chlorideplus ten and twenty percent acetone. Crystallization of the firstfraction from a mixture of acetone and Skellysolve B hexanes gave 3,11diketo 5a hydroxy 6 8-buoro-16a-methyl- 17(20)-allopregnen-21-oic acidmethyl ester.

EXAMPLE 4 3-ethylene glycol ketal of3,11-diket0-5a-hydr0xy-6B-fluarc-16m methyl-17(20)-[cis]allopregnen-ZI-oic acid methyl ester A mixture of 1.9 grams of 63-fiuoro-3,ll-diketo-5ahydroxy-16u-methyl-17 (20)-[cis]-allopregnen-21-oate, 5 9 milligrams of para-toluenesulfonic acidmonohydrate and 31 milliliters of distilled ethylene glycol was added to800 milliliters of benzene. The mixture was stirred and refluxed for twohours, with the condensate passing through a water trap to remove thewater. Then the mixture was cooled, washed with water and evaporated todryness to give a crude solid which on recrystalliaztion from a mixtureof acetone and hexanes gave the 3-ethylene glycol ketal of 3,11 diketo5a-hydroxy-6B-fluoro-l6a-methyl- 17(20)-[cis]-allopregnen-Zl-oic acidmethyl ester.

Following the above procedure, substituting other dihydric alcohols forethylene glycol, for example, 1,2- propylene glycol, 2,3-butanediol,1,3-butanediol and 2,3- pentanediol, is productive of the respective3-alkylene ketals of 3,11 diketo 5a-hydroxy-6fl-fluoro-lfia-methyl-17(20)-allopregnen-21-oic acid methyl ester.

EXAMPLE 5 To a solution of 1.96 grams of the 3-ethylene glycol f 15 tionwas washed with water, dried and evaporated to dryness under reducedpressure. The crude solid residue was crystallized fromacetone-Skellysolve B hexanes to give the 3-ethylene glycol ketal of5a,llti,21-trihydroXy-6,8-fluoro-16a-methyl-17(20)-[cis]-allopregnen-3-one.

EXAMPLE 6 The 3-ethylene glycol ketal f 01,1 1 18,21 -trihydr0xy-6flflu0r0-16a-methyl-17(20 [cis] -all0pregnen-3 one 21- acetate 0.87 gramof the S-ethylene ketal of 5a,ll 3,21-ifihydroxy6,8-fiuoro-16a-methyl-17(20)-[cis]-allopregnen- 3-one was dissolved inten milliliters of acetic anhydride and ten milliliters of pyridine. Thesolution was maintained sixteen hours at room temperature and thenpoured into ice water to give the 3-ethylene glycol ketal of5a,11fl,2l-trihydroxy-6 8-fluoro-l6u-methyl-17(20)[cislallopregnen-3-one 21-acetate.

Similarly, other 2l-organic carboxylic acid esters of5u,11,8,21-trihydroXy-6p-fluoro-16u-methyl-l7 [cislallopregnen-S-one3-ethylene ketals can be prepared wherein the 21-acyloXy group isformyloxy, propionyloxy, butyryloxy, valeryloxy, heXanoyloXy,heptanoyloxy, octanoyloxy, benzoyloxy, phenylacetoxy, or the like, bycontacting the 3-ethylene ketal of5a-11/3,21-trihydroXy-6fifluoro-16a-methyl-17(20)-[cis]-allopregnen-3one with the appropriate acylating agent, e.g., the anhydride or acidhalide of the selected acid in a solvent such as benzene, toluene,acetic acid, or the like, perferably in the presence of pyridine or asimilar amine.

ErAMPLE 7 The 3-ethylene glycol ketal 0f 5a,11,8,17a,21-tetrahydroxy-6B-flu0r0-16a-methylall0pregnane-3,20-dione 21-acetate To a solution of0.93 gram of the 3-ethylene glycol ketal of 50a, llfl-dihydroxy6B-fluoro-16amethyl-17(20)- allopregnen-3-one 2l-acetate in 35milliliters of tertiary butyl alcoholwas added one milliliter ofpyridine, 2.75 milliliters of two molar N-methylmorpholine oxideperoxide (U.S. 2,769,823) in tertiary butyl alcohol, and 13.1 milligramsof osmium tetroxide in tertiary butyl alcohol (9.1 milliliters oftertiary butyl alcohol solution contain ing 1.44 milligrams osmiumtetroxide per milliliter). The solution was stirred for a period ofeighteen hours and fifteen milliliters of five percent sodiumhydrosulfite was added. Stirring was continued for an additional tenminutes, at which time 0.7 gram of finely ground synthetic magnesiumSilicate was mixed into thesolution for a period of twenty minutes andthen removed by filtration. The filtrate was evaporated to dryness underreduced pressure at a temperature of less than fifty degrees centigrade.The residue was dissolved in methylene chloride, washed with water,dried and evaporated to dryness. The residue was crystallized fromacetone-Skellysolve B hexanes to give the 3-ethylene glycol ketal of5a,11fl,17a,21-tetrahydroXy-6B-fiuoro-16a-methylallopregnane-3,20 dione21- acetate.

EXAMPLE 8 6a fluoro-I 1 3,1 7u,21-trihydroxy-1 6 a-methyll-pregn ene-3,20-dione 21-acetate A solution of 0.144 gram of the 3-ethylene glycolketal of 5a,11B,17a,21 tetrahydroxy 6 8fluoro-l6ot-methylallopregnane-3-20-dione ZI-acetate in twelvemilliliters of chloroform and 0.1 milliliter of absolute alcohol wascooled to minus ten degrees centigrade in an ice-salt bath and a streamof anhydrous hydrochloric acid was gently bubbled through the solutionfor 2.5 hours while the temperature was maintained between minus fiveand minus fifteen degrees centigrade. The solution was then diluted with25 milliliters of chloroform, washed with dilute sodium bicarbonate andwater, dried over anhydrous so dium sulfate, and evaporated to drynessunder reduced pressure at sixty degrees centigrade or less to give 6al6fiuoro-l1p],1701,21-trihydroxy-16a-methyl-4-pregnene-3,20- dione21-acetate.

EXAMPLE 9 du-fluoro-l 1 p, I 70 2] -Irihydr0xy-1 6a-methy L1 ,4-pregnadiene-3,20-di0ne A medium consisting of one percent dextrosehydrate, two percent cornsteep liquor of sixty percent solids and tapwater was adjusted to pH 4.9 with sodium hydroxide. The medium was steamsterilized at fifteen pounds pressure for thirty minutes, cooled, andthen inoculated with a 24-hour growth, from spores, of Septomyxaafiinis, A.T.C.C. 6737. The medium was agitated, and sparged withsterile air at the rate of one-tenth volume of air volume of medium perminute. At the end of 24 hours of fermentation at room temperature, thepH was about 7.4. To this culture there was added a solution of6a-fluoro- 1 1 8,170)l-trihydroxy-16a-methyl-4-pregnene-3,20 dione2l-acetate dissolved in a minimal amount of diethylformamide. Thesolution was prepared by dissolving five parts of the steroid in partsof the solvent and adding about ten cc. of the solution per liter of themedium. Fermentation was continued for a period of 48 hours whereuponthe mycelium and beer were extracted thoroughly with methylene chloride.The extract was washed with sodium bicarbonate solution and then withwater, dried and concentrated in vacuo to give 6a-fluoro-llfi,l7u,21-trihydroxy-16wmethyl-1,4-pregnadiene-3,20-dione.

Following the procedure of Example 9, but substituting as startingmaterial 6a-fiu0ro-11B,17a,21-trihydr0xyl6a-methyl-4-pregnene 3,20 dione21-acetate there was likewise produced 6ot-fitl0lO-llfi',l7ot,2l-trihydr0Xy-16amethyl-1,4-pregnadiene-3,20-dione.

EXAMPLE 1O 6a-fluor0-1 1 6,1 711,21 -trihydroxy-1 6a-methyl-1 ,4-

- pregnene-3,20-dione A solution of 1.1 grams of6a-fluoro-11,6,17a,21-trihydroxy-l6a-methyl-4-pregnene-3,20-dione21acetate, one gram of potassium bicarbonate, 100 milliliters ofmethanol and fifteen milliliters of Water were mixed together and purgedwith nitrogen to remove dissolved oxygen while stirring at 25 degreescentigrade for four hours. The solution was then neutralized by additionof acetic acid and distilled under vacuum to remove the methanol. Theresidue was extracted with 100 milliliters of methylene chloride, andthe extract was dried over sodium sulfate to give a solution of6u-fiu0ro-11B,17a,2l-trihydroxy 16a-methyl-4-pregnene-3,ZO-dione whichwas freed of solvent: by evaporation.

EXAMPLE 11 dot-fluoro-l 113,170:,21-trihydr0xy-16a-methyl-L4-pregnadiene-3,20-dione 21 -acetatc 1.5 grams of 6a-fluo'ro-llB,17a,2l-trihydroXy-lGa-methyl-1,4-pregnadiene-3,20-dione was dissolvedin twentymilliliters of pyridine and fifteen milliliters of acetic anhydride and the mixture heated at forty degrees centigrade for fourhours. The solution was cooled and then slowly diluted with water. Theprecipitated steroid was removed by filtration, washed with water anddried to give 6a-fluoro-1 1/3,Hall-trihydroxy-lfiu-metbyl-lA-pregnadiene-3,20-dione 2l-acetate.

60c fluoro l15,17u,21 trihydroxy 16a methyl-1, 4-pregnadiene-3,20-dioneis converted to other 21-esters by reaction with the appropriate acidanhydride, acid chloride, or bromide or by other methods known in theart, e.g., by ester exchange, acid, in the presence of an esterificationcatalyst, etc., to produce 6oc-fiu0I'O-l1l3,17oz,2l-trihydroxy-l6a-methyl-1,4-pregnadiene-3 ,20-di0ne 21- acylates whichinclude those wherein the acyl radical of the 21-acylate group is theacyl radical of, for example, a lower aliphatic acid, e.g., formic,propionic, butyric, isobutyric, Valerie, isovaleric, trimethylacetic,Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic,triethylacetic, heptanoic, octanoic, ot-ethylisovaleric, a cyclic acid,e.g., cycloproplideneacetic, a cycloaliphatic acid, e.g.,cyclopentylformic, cyclopentylacetic, B-cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, p-cyclohexyl propionic, an aryl oralkaryl acid, e.g., benzoic 2, 3, or 4- methylbenzoic, 2,3-, 2,4-, 2,5-,2,6-, 3,4- and 3,5-dirnethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic 2,4,6-triethylbenzoic, ot-naphthoic,3-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic,phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (whichcan be" converted to water soluble, e.g., sodium salts), e.g., succinic,glutaric, a-methylglutaric, fi-methylglutaric, 5,,3- dimethylglutaric,adipic, pimelic, suberic, a hydroxyacid, e.g., glycolic, lactic, citric,tartaric, d-maleic, d-glyceric, mannonic, gluconic, salicyclic,2,3,4-tri-methoxybenzoic, anapthoxyacetic, or other acyl acid.

Similarly, fia-fluoro-l 1B,17ot,21-trihydroxy-16ot-methyl-4-pregnene-3,20-dione is converted to any of the other esters named inthe paragraph following Example 11 by substituting 1 1B,17a,21-trihydroxy-16u-methyl-4-pregnene- 3,20-dione as the startingcompound in the acylation reaction.

EXAMPLE 12 6 a-fluoro-l 6 a-m ethy l-17a,21-dihydr0xy-1,4-pregnadiene-SJ 1,20-trine 21 -acetate To a solutionof 2.5 millimoles of 6ot-fiuoro-ll 3,l7a,ZI-trihydroxy-16a-methyl-1,4-pregnadiene-3,ZO-dione 21- acetate and twomilliliters of pyridine in 75 milliliters of tertiary butanol was added500 milligrams of N-bromoacetamide. The reaction mixture was maintaniedat room temperature for about sixteen hours whereupon the solution wasdiluted with fifty milliliters of water containing 500 milligrams ofsodium sulfite, and the mixture was then concentrated at reducedpressure to about forty milliliters. The distillation residue wasrefrigerated, filtered, and the filter cake Was washed with water andthen dried. It consisted of 6a-fluoro-l6ot-methyl-17a,2l-dihydroxy-l,4-pregnadiene-3,l1,20-trione 21-acetate.

EXAMPLE 13 6 u-fluoro-l 6ot-methyl-1 711,21-dihydr0xy-4-pregnene-3,11,20-tri0ne 21-acetate Following the procedure of Example 12, butsubstituting 6a-fluoro-1lfl,l7a,2l-trihydroxy 16amethyl-4-pregnene-3,20-dione 21-acetate as starting compound, there isthus produced 6a-flu0ro-1Got-methyl-17a,21-dihydroxy- 4-pregnene-3,11,20-trione 2l-acetate.

Similarly, substituting another 21-acylate of 6a-fluoro-11B,l7a,21-trihydroxy 16a methyl 1,4 pregnadiene- 3,20-dione or21-acylate of6ot-fluoro-11B,17et,2ltrihydroxy-l6a-methyl-4-pregnene-3,20-dionewherein the acyl radical is, e.g., that of an acid named in theparagraph following Example 11, as the starting compound in theoxidation reaction described in Example 12, there is thus produced thecorresponding 2l-acylate of6ot-fl1l0I'O-16ctmethyl-l7a,21-dihydroxy-1,4-pregnadiene-3,11,20 trioneand of 6OL-fillOl'O-160L-methy1-170t,21 dihydroxy 4pregnene-3,11,20-trione, respectively.

EXAMPLE 14:

6 ot-flzroro-l 6u-methyl-1 7 (1,21 -dihydroxy-1 ,4 ,9 (I 1pregnatriene-3,20-di0ne 21 -acetate To a solution of 8.5 grams of6ot-fluoro-11 8,l7u,21-trihydroxy-16amethyl-1,4-pregnadiene 3,20 dione21- acetate in 42.5 milliliters of pyridine was added 5.63 grams ofN-bromoacetamide. After standing at room temperature for a period offifteen minutes, the reaction solution was cooled to five to ten degreesCentigrade and sulfur dioxide gas was passed over the surface of thesolution while shaking the flask until the solution gave no color withacidified starch-iodide paper. During the addition of the sulfurdioxide, the reaction mixture became warm. The temperature was keptunder thirty degrees Centigrade by external cooling and by varying therate of sulfur dioxide addition. Thereafter to the reaction mixture wasadded 400 milliliters of ice water and the resulting precipitatecollected by filtration. This material was recrystallized fromacetone-Skellysolve B hexanes to give 6OL-fll10l0 16amethyl-17a,21-dihydroxy-1,4,9(11)- pregnatriene-3,20-dione 21-acetate.

EXAMPLE 15 6 a-fluoro-l 6ot-methyl-1 704,21 dihydroxy-4 ,9 1 Ipregnadiene-3,20-dione 21 -acetate Following the procedure of Example14, but substituting 6afluoro-l1/3,17a,21-trihydroxy-l6a-methyl-4-pregnene-3,20-dione21-acetate as the starting compound, there is thus produced6a-fiuoro-16a-methyl-l7a,21-dihydroxy-4,9 (l l )-pregnadiene-3,20-dione21-acetate.

Similarly, substituting another 21-acylate of 6at-fluoro-1lB,17a,2l-trihydroxy 16oz -methyl 1,4 pregnadiene- 3,20-dione or a21-acylate of6a-fluoro-11fi,17ot,2l-trihydroxy-l6a-methyl-4-pregnene-3,20-dionewherein the acyl radical is, e.g., that of an acid named in theparagraph following Example 11, as the starting compound in thedehydration reaction described in Example 11, there is thus produced thecorresponding 21-acylate of Got-fluoro- 16ot-methyl-l7ot,2l dihydroxyl,4,9(11) pregnatriene- 3,20-dione and of 6a-fluoro-16a-methyl-17a,21-dihydroxy-4,9 1 1 -pregnadiene-3 ,20-dione, respectively.

EXAMPLE 16 To a solution of 5.68 grams of 6a-fluoro-l6wmethyl-17a,21-dihydr0xy-1,4,9(11)-pregnatriene-3,20 dione 21- acetate inmilliliters of methylene chloride and 250 milliliters of tertiary butylalcohol was added a solution of fourteen milliliters of 72 percentperchloric acid in 100 milliliters of water followed by a solution of2.34 grams of N-bromo-acetamide in sixty milliliters of tertiary butylalcohol. After stirring the reaction mixture for fifteen minutes, asolution of 2.8 grams of sodium sulfite in milliliters of water wasadded and the reaction mixture was concentrated to a volume of about 500milliliters under reduced pressure at about fifty degrees centigrade.The concentrate was cooled in an ice bath and while stirring 500milliliters of water was added. After stirring for a period of one hour,the precipitated product was isolated by filtration, and the cake washedwith water and air-dried to give6u-fluoro-9a-bromo-11/8,17a,21-trihydroxy-16a-methyl-l,4-pregnadiene-3,2Odione 21 acetate.

EXAMPLE 17 6a-flu0r0-9a-bromo-1 1 9,1 7a,21-trihydr0ocy-1 6 tat-methyl-4-pregnene-3,20-dione 21 -acetate Following the procedure of Example 16,but substituting 6a-fluoro 16oz methyl 17u,2l dihydroxy-4,9(l1)-pregnadiene-3,20-dione 2l-acetate as the starting compound, there isthus produced 6oz fluoro 9a bromo- 11B,17a,21-trihydroxy 16a methyl 4pregnene-3,20- dione 21-acetate.

Similarly, substituting another 21-acylate of 6a-fluoro-16u-methyl-17a,21 dihydroxy 1,4,9(11) pregnatriene- 3,20-dione or a21-acy1ate of 6a-fluoro-17a,21-dihydroxy-16ot-methy1-4,9(1l)-pregnadiene-3,20 dione wherein the acyl radical is,e.g., that of an acid named in the pa agraph following Example 11, asthestarting compound in the reaction described in Example 16, there is thusproduced-the corresponding 2l-a'cylate of6a-fill0r0-9abromo-l1B,17a,21-trihydroxy-16a methyl 1,4pregnadiene-3,20-dione and of 6a-fiuoro-9a-bromo-1113,17a,21-trihydroxy-l6u-methyl-4-pregnene 3,20 dione, respectively.

Substituting N-chlorosuccinimide for the N-bromoacetamide in thereactions described in Examples 16, 17 and the paragraph following isproductive of the corre- 19 sponding 9a-chloro compounds, e.g.,6oc-fil101O-9a-Chl0f0- l1B,17u,2l-trihydroxy-l6ot-methyl-1,4-pregnadiene3,20- dione 21-acetate and 6a-fiuoro-9a-chloro-1 1 18,111,21-trihydroxy-l6ot-rnethyl-4-pregnene-3,20 dione 2l-acetate.

EXAMPLE 18 6a-fluoro-9fiJ1 3-ep0xy-1 70;,21 -dihydrxy-1 6 u-m'e thy l-1,4-pregnadiene-3,ZO-dione 21 -acetate To a solution of 6.78 grams of6a-fiuoro-9m-bromol1,3,17a,21-trihydroxy-16a-methyl-1,4-pregnadiene3,20- dione ZI-acetate in 175 milliliters of acetone wasadded 6.78 gramsof potassium acetate and the resulting suspension was heated underreflux for a period of seventeen hours. The mixture was thenconcentrated to approximately sixty milliliters volume at reducedpressure on the steam bath, diluted with water and extracted withmethylene chloride. The methylene chloride extracts were combined,washed with water, dried over anhydrous sodium sulfate and evaporated.The residue was redissolved in methylene chloride and chromatographedover 500 grams in Florisil anhydrous magnesium silicate. The column waseluted with one-liter portions of hexanes (Skellysolve B) containingincreasing proportions of acetone. There was thus eluted6a-fluoro-9fi,llB-epoxy-l6a-methyl-l7u,2l-dihydroxy-l,4-pregnadiene-3,ZO-dione21-acetate which was freed of solvent by evaporation of the eluates.

EXAMPLE 19 4-pregnene-3,20-di0ne 21 -acetate Following the procedure ofExample 18, but substituting 6(l-fluOI'O-90t-bI'O1TlO 1113,l7a,21trihydroxy 16amethyl-4-pregnene-3,ZO-dione 21-acetate as the startingcompound, there is thus produced 6a-fiu0ro-9,8,1lfl-epoxyl6a-rnethyl-l7a,2l-dihydroxy-4-pregnene-3,2O dione 2lacetate.

Similarly, substituting another 21-acylate of 6a-fluoro- 9ozbromo-l1,8,17a,21-trihydroxy-lfiu-methyl-lA-pregnadiene-3,20-dione or a2l-acylate of Ga-HUOIO-QwblOmO- 11,8,17a,21trihydroxy-l6a-methyl-4-pregnene-3,ZO-dione wherein the acyl radical is,e.g., that of an acid named in the paragraph following Example 11, asthe starting compound in the reaction described in Example 18, there isthus produced the corresponding 21-acylate'of fia-flLlOlO- 95,115 epoxyl6a-methyl-17a,2l-d'ihydroxy-l,4-pregnadiene-3,20-dione and of6a-fil10rO-9fl,llB-BPOXY-16m-Ill6thyl-17u,2l-dihydroxy-4-pregnene-3,ZO-dione,respectively.

EXAMPLE 20 6a,9ot,diflu0r0-1];8,1 70:,21 -trihya'roxy-I 604-10261113 1-1,4-pregnadiene-3,20-dione-21acetate To approximately 1.3 grams ofhydrogen fluoride contained in a polyethylene bottle and maintained atminus sixty degrees centigrade was added 2.3 milliliters oftetrahydrofuran and then a solution of 500 milligrams (0.0012 mole) of60:fiuoro-9/3,1lfi-epoxy-16u-methyl-17a,2l-dihydroxy-1,4-pregnadiene-3,20-dione21-acetate in two milliliters of methylene chloride. The steroidsolution was rinsed in with an additional one milliliter of methylenechloride. The light red colored solution was then kept at approximatelyminus thirty degrees centigrade for one hour and at minus ten degreesfor two hours. At the end of this period it was mixed cautiously with anexcess of cold sodium bicarbonate solution and the organic materialextracted with the aid of additional methylene chloride. The combinedextracts were washed with water, dried over anhydrous sodium sulfate andconcentrated to approximately 35 milliliters. The solution waschromatographed over 130 grams of Florisil anhydrous magnesium silicate.The column was developed with 260-milliliter portions of hexanes(Skellysolve B) containing increasing proportions of acetone. There wasthus eluted 6a,9a-difiuoro 11fi,17x,21 trihydroxy 16ozmethyl-1,4-pregnadiene-3,20-dione 21-acetate which was freed of solventby evaporation of the eluate fractions.

EXAMPLE 21 Following the procedure of Example 20, but substituting 6afluoro-9,3,1IB-epoxy-lGot-methyl-17u,21-dihydroxy-4- pregnene-3,20-dione2l-acetate as the starting compound, there is thus produced60:,904-dlfl110f0-11y3,17a,21-t1ihydroxy-l6a-methyl-4-pregnene-3,20-dione21-acetate.

Similarly, substituting another 21-acylate of 6a-tluoro- 9 8,115 epoxy:,21-dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dio-ne or a 21-acylate of6a-fluoro-9fi,llflepoxy 170:,21 dihydroxy 16a-methyl-4-pregnene-3,20-dione wherein the acyl radical is, e.g., that of an acid named in theparagraph following Example 11, as the starting compound in the reactiondescribed in Example 17, there is thus produced the corresponding21-acylate of 60:,90: difluoro 1l}3,17oc,21 trihydroxy-lGtx-methyl-IA-pregnadiene-3,20-dione and of 6a,9ot-difluoro-1lfi,7a,21- trihydroxy 16amethyl 4-pregnene-3,20-dione, respectively.

EXAMPLE 22 A solution was prepared containing one milliliter of aceticacid, fifty milligrams of 60:,9ot-difi11010-11B,17a,21-trihydroxy-l6ot-methyl-1,4-pregnadiene-3,20-dione 21-acetate, twentymilligrams of chromic anhydride. and one drop (approximately fiftymilligrams) of water. This mixture was shaken several times at roomtemperature and allowed to stand for four hours. Thereafter it waspoured into ten milliliters of water and refrigerated for twenty hoursat about five degrees centigrade. The steroid which separated from theaqueous mixture was collected on filter paper and dried to give6a,9a-difluoro-16u-rnethyl-17a,2l-dihydroxy-1,4-pregnadiene-3,11,20-trione 21-acetate.

EXAMPLE 23 Following the procedure of Example 22, but substituting6a,9ot difiuoro-l1B,17a,21-trihydroxy-16a-methyl-4- pregnene-3,20-dione2l-acetate as the starting compound, there is thus produced6a,9a-difluoro-16a-methyl-171,21- dihydroXy-4-pregnene-3,1 1,20-trioneZl-acetate.

Similarly, substituting another 2l-aeylate of 6lx,9ocdifiuoro11fi,l7rx,21 trihydroxy 16a methyl-1,4-pregnadiene-3,20-dione or a21-acylate of 6a,9a-difluoro-llfi, l7a,2l trihydroxy 16a methyl4-pregnene-3,20-dione wherein the acyl radical is, e.g., that of an acidnamed in the paragraph following Example 11, as the starting compound inthe oxidation reaction described in Example 22, there is thus producedthe corresponding 21-acylate of 60:, 9oz difluoro 16ozmethyl-17a,21-dihydroxy-1,4pregnadiene-3,11,20-trione and of60:,9oc-diflll0t0-l6rx-methyl-l7oc, 21-dihydroxy-4-pregnene-3,11,20-trione, respectively.

EXAMPLE 24 Three and one-quarter (3.25) grams of 6a,9a-difiuoro-11,8,l7a,21 trihydroxy-16a-methyl-l,4-pregnadiene-3,20- dione ZI-acetatewas dissolved in 325 milliliters of methanol, previously purged ofair-oxygen by passing nitrogen through it for ten minutes and theretowas added a solution of 1.63 grams of potassium bicarbonate in thirtymilliliters of water, similarly purged of oxygen. The mixture wasallowed to stand at room temperature for a period of five hours in anitrogen atmosphere, thereupon neutralized with 2.14 milliliters ofacetic acid in forty milliliters of water. The mixture was concentratedto approximately one-third volume at reduced pressure on asixty-degree-centigrade water-bath. T hereupon 250 milliliters of waterwas added and the mixture chilled. The

crystalline product was collected on a filter, washed with water anddried to give6ot,9ot-difluoro-l1B,l7a,2l-trihydroxy-16et-methyl-l,4-pregnadiene-3,20-dione.

EXAMPLE 25 Following the procedure of Example 24, but substituting6:2,90: difluoro-ll 8,l7a,2l-trihydroxy-l6a-methyl-4-pregnene-3,20-dione 2l-acetate as the starting compound, there is thusproduced6u,9ot-difluoro-llfl,l7ot,2l-trihydroxy-16amethyl-4-pregnene-3,20-dione.

Similarly 6a,9a-difluoro-16a-methyl-17a,21-dihydroxy-4-pregnene-3,ll,20-trione 2l-acetate is hydrolyzed to 6a, 9a difluoro16a-methyl-l7a,2l-dihydroxy-4-pregnene- 3,1 1,20-trione and6a,9u-difluoro-16a-methyl-17ot,2l-dihydroxy-l,4-pregnadiene-3,11,20-trione2l-acetate is hydrolyzed to6a,9a-difluoro-16a-methyl-l7ot,2l-dihydroXy-1,4-pregnadiene-3,11,20-trione. The corresponding 9a-Chl0l0 compounds aresimilarly prepared by hydrolysis of their 21 acetates, e.g.,6a-fluoro-9a-chloro-11fl,17a,21-trihydroxy 16amethyl-1,4-pregnadiene-3,20-dione and 6afluoro 9oz chloro 118,l7ot,2l-trihydroxy-l6a-methyl-4- pregnene-3,20-dione are prepared from6a-fluoro-9achloro l1fl,17a,21 trihydroxy-l,4-pregnadiene-3,2l-dione21-acetate and from GOL-flUOI'O-QOL-ChlOIO l1fi,17at,21- trihydroxy16a-methyl-4-pregnene-3,20-dione 2l-acetate, respectively.

EXAMPLE 26 6a,9a-difluor0-J 113,1 7a,21 -trihydroxy-1 6ot-methyl-1,4-pregnadiene-3,20-dine 21 -pr0pi0nate A solution was prepared containingfifty milligrams of 611,904 difluoro 1l,8,17ot,21trihydroxy-16m-methyl-1,4- pregnadiene-3,20-dione in one milliliter ofpyridine and one milliliter of propionic anhydride. The solution wasallowed to stand at room temperature for a period of 21 hours and wasthereupon poured into ten milliliters of water. The reaction mixture wasthen extracted with three ten-milliliter portions of methylene chloride,the methylene chloride extracts were combined, washed with water, driedover anhydrous sodium sulfate and evaporated to give a residue of6u,9a-difluoro-1l5,l7a,2l-trihydroxyl6a-methyll,4-pregnadiene-3,20-dione 21-propionate.

EXAMPLE 27 6 a,9a-diflu0r0-1 1,8,1 7u,21-trihydr0xy-16a-methyl-4-pregnene-3,20-dione 21 -propi0nale Following the procedure of Example26, but substituting 6a,9a difluoro ll5,l7a,21 trihydroxy 16ccmethyl-4-pregnene-3,20-dione as starting compound, there is thusproduced 6a,9a-difluoro-11B,l7u,2l-trihydroxy-16a-methyl-4-pregnene-3,20-dione 2l-propionate.

Similarly, 6u,9ot-difluoro-16et-methyl-l7a,2l-dihydroxy-1,4-pregnadiene-3,l1,20-trione is converted to 60,9a-difluoro 16a methyll7a,21-dihydroxy-1,4-pregnadiene- 3,11,20 trione 21-propionate and6ot,9oz difluoro 16amethyl 17a,21 dihydroxy-4-pregnene-3,l1,20-trione isconverted to 6u,9nt-difluoro-l6a-methyl-l7ct,21-dihydroxy-4-pregnene-3,1 1,20-trione 21-propionate.

Similarly, substituting another acylating agent for the propionicanhydride in the esterification of 6a,9a-difluoro 11/3,17a,21trihydroxy-16a-methyl-1,4-pregnadiene- 3,20-dione or6nt,9a-difluoro-l118,17a,2l-trihydroxy-l6amethyl-4-pregnene3,20-dione,e.g., in the manner described in the paragraph following Example 11,there is thus produced other 2l-acylates of 6a,9ot-difluoro-l1;8,170:,21 trihydroxy 16ot-methyl-l,4-pregnadiene-3,20-dione and6a,9ot-difluoro l1B,l7a,2l-trihydroxy-l6a-methyl-4-pregnene-3,20-dione,respectively, wherein the acyl radical is, e.g., that of an acid namedin the paragraph following Example 6. The corresponding ll-ketocompounds are similarly converted to their corresponding 21- acylateesters.

EXAMPLE 28 A solution was prepared containing one gram (2.6 millimoles)of 6a fluoro 11,8,l7a,2l trihydroxy-16amethyl-1,4-pregnadiene-3,20-dionein seven milliliters of pyridine. This solution was cooled to zerodegrees centigrade and treated with 0.3 milliliter of methanesulfonylchloride. Thereafter the solution was allowed to stand at zero to fivedegrees centigrade for a period of two hours, after which it was dilutedwith water and extracted with three ZS-milliliter portions of methylenechloride. The extracts were combined, washed with cold dilutehydrochloric acid until the aqueous layer had a pH of two to three, thenwashed again with cold sodium bicarbonate solution, water and finallydried over anhydrous sodium sulfate. Evaporation of the methylenechloride extract at reduced pressure left a residue of60t-flll0l'O-11B,17a,21- trihydroxy 16ozmethyl-1,4-pregnadiene-3,20-dione-21- methanesulfonate.

Similarly, substituting 6a-fluoro-llfi,l7a,2l-trihydroxy-16u-methyl-4-pregnene-3,20-dione as the starting compound, there is thusproduced 60t-fiUOI'O-11,B,17(Z,21-tl'ihydroxy16a-methyl-4-pregnene-3,20=dione 2l-methanesulfonate. The coresponding9a-fluoro and 9a-chloro 21- methanesulfonate compounds are similarlyprepared.

EXAMPLE 29 Similarly, substituting 6ot-fluoro-llB,l7a,2l-trihydroxy-16ot-methyl-4-pregnene-3,20-dione ZI-methanesulfonate as the startingcompound, there is thus produced 6a-fiuoro- 116,17a dihydroxy 16amethyl-21-iodo-4-pregnene- 3,20-dione. The 9u-chloro and 9a-fluoroanalogues of both of these compounds are similarly prepared.

EXAMPLE 30 61,21 -d i fluoro-l 1,3,1 7a-dihydroxy-16ot-methyl-L4-pregnadiene-3 ,2 O-dione One gram of6u-fluoro-l1B,Hot-dihydroxy-l6a-methyl-2liodo-1,4-pregnadiene-3,20-dione was dissolved in 150 milliliters ofboiling acetonitrile. After cooling to forty degrees centrigrade, thesolution was protected from light and 0.8 milliliter of a fifty percentaqueous solution of silver fluoride was added under stirring. Stirringwas continued for one hour at about forty degrees centigrade, then 0.7milliliter of silver fluoride solution was added. After another hour ofstirring another 0.7 milliliter portion of aqueous silver fluoridesolution was added. Heating and stirring was then continued for a periodof two hours. The brown mixture was then filtered through a bed ofdiatomaceous earth (Celite) and the filtrate evaporated at reducedpressure at a bath temperature of fifty degrees centrigrade. The brownresidue was thoroughly extracted with two -milliliter portions of warmmethylene chloride, the combined extracts washed with water and driedover anhydrous sodium sulfate. The dried solution was concentrated toapproximately 100 milliliters and then chromatographed over fifty gramsof magnesium silicate (Florisil). The column 23 was eluted with hexanescontaining increasing proportions of acetone to give60:,2l-difi110IO-l15,17oc-dihYd1'0XY'loot-methyl-l,4-pregnadiene-3,ZO-dione.

In the same manner as given in Examples 28 to 30, 60:,90: difluorollfi,l7a,21 trihydroxy 16oz. methyl- 1,4-pregnadiene-3,20-dione wasconverted to 6a,9a21- tn'fiuoro 116,17a dihydroxy 4 16a methyl 1,4pregnadiene-3,20-dione.

Similarly, substituting 6a fluoro 115,170; dihydroxy-16a-methyl-2l-iodo-4-pregnene-3,20-dione starting compound, there isthus produced 6oz,21-difluoro-ll;8,l7otdihydroxy 16amethyl-4-pregnene-3,20 dione. 60c,9ot,2ltrifluoro 115,17 dihydroxy 16ozmethyl 4 pregnene-3,20-dione is similarly prepared from 60,9oc-dlfluoro116,17 dihydroxy 160a methyl 21 iodo- 4-pregnene-3,20-dione. Thecorresponding 9ot-chloro compounds are similarly prepared.

EXAMPLE 31 601,21 -difluoro-1 1 [3,1 7a-dihydr0xy-1 6u-methy l-1,4-pregnadiene-3,20-dione A solution of one gram of6a-fiuoro-11fi,17a,21-trihydroxy-16a methyl 1,4 pregnadiene 3,20 dione21- methanesulfonate and 0.50 gram of anhydrous potassium fluoride inten milliliters of dimethylsulfoxide was heated at 100 degreesCentigrade for twelve hours. The cooled solution was diluted with Waterand then extracted with methylene chloride. The extracts were dried andchromatographed over magnesium silicate in the manner described inExample 30 to give substantially pure 6u,2ldifluoro 11 8,1701 dihydroxy16cc methyl 1,4 pregnadiene-3,20-dione.

EXAMPLE 32 6:1,21 -diflur0-1 6a-methyl-1 7a-hydr0xy-1 ,4-pregnadiene-3,11,20-tri0ne A solution was prepared containing 0.5 gram of 604,21-difiuoro 11{3,l7u dihydroxy 16a methyl 1,4 pregnadiene-3,20-dione, 0.15gram of chromic acid, ten milliliters of glacial acetic acid andone-half milliliter of water. This mixture was stirred and thenmaintained for eight hours at room temperature. Thereafter the mixturewas poured into fifty milliliters of ice water, neutralized by theaddition of dilute sodium hydroxide and the thusobtained precipitatecollected on a filter and recrystallized three times from a mixture ofethyl acetate and Skellysolve B hexanes to give6u,2l-difluoro-l-6a-methyl- 17a-hydroxy-1,4-pregnadiene-3 1 1,20-trione.

In the same manner given in Example 32, 6a,9oc,2ltrifluoro 115,170dihydroxy -l=6o methyl 1,4 pregnadiene-3,20-dione was oxidized to6,9a,21-trifluoro- 16a-methyl-l7a-hydroxy-l,4-pregnadiene-3,l1-20-trione.

Similarly, 6a,2l-difluoro-l6u-methyl 17 on hydroxy-4-pregnene-3,ll,20-trione is prepared from 6a,.21-difluoro-1113,17a-dihydroxy-16a-rnethy1-4-pregnene-3,ZO-dione and 6a,9cx,2ltrifluoro 16oz methyl 17a hydroxy 4- pregnene-3,l1,20-trione is preparedfrom 6a,9oc,2ltflfluoro 1113,17 dihydroxy 16a methyl 4 pregnene-3,20-dione. The corresponding 9oc-Cl1l0l'0 compounds are similarlyprepared.

EXAMPLE 33 6a-fluor0-11p,17a-dihydroxy-16u-methyl-L4-pregnadiene-3,20di0ne 150 milligrams ofGot-fillOIO-l113,17oc-dll1Ydl0XY-l6ozmethyl-2l-iodo-l,4-pregnadiene-3,ZO-dionewas slurried with five milliliters of acetic acid and stirred for aperiod of 45 minutes. Then an aqueous solution of 250 rnilli grams ofsodium thiosulfate pentahydrate was added causing the iodine color todisapepar. Additional water was added (fifty milliliters) and themixture extracted with three ZS-milliliter portions of methylenechloride. The methylene chloride extracts were combined, washed withwater and cold sodium bicarbonate solution until all acetic acid wasneutralized. After drying over anhydrous sodium sulfate, the solutionwas concentrated to approximately fifteen milliliters andchromatographed over ten grams of magnesium silicate (Florisil). Thecolumn was developed With hexanes containing increasing proportions ofacetone, to give substantially pure6a-fluoro-11fl,17adihydroxy-16u-methyl-l,4-pregnadiene-3,20-dione.

Following the procedure of Example 33, 60,9oc-dlfll10l'0- 115,17dihydroxy 16o: methyl 21 iodo 1,4 pregnadiene-3,20-dione was convertedto 6a,9a-difluorollfi,l7oc dihydroxy 16oz methyl 1,4 pregnadiene-3,20-dione.

Similarly, 6a fluoro-11,6,Not-dihydroxy-1-6m-methyl-4-pregnene-3,20-dione is prepared from6oc-flu0r0-1lfi-17ocdihydroxy-l6a-methyl-21-iodo-4-pregnene-3,20-dioneand 6a,9u difluoro 115,170; dihydroxy 16a. methyl 4- pregene-3,20-dionefrom 60$,90rrdlflll0l0 115,170 dihydroxy 16oz methyl21-iodo-4-pregnene-3,20-dione. The corresponding Qa-ChlOl'O compoundsare similarly prepared.

EXAMPLE 34 A mixture was prepared containing 0.3 gram of 60a fluoro 113,17a dihydroxy 16a methyl 1,4 pregnadiene-3,20-dione, milligrams ofchromic anhydride, ten milliiters of glacial acetic acid and one-halfmilliliter of water. This mixture was stirred and thereupon maintainedfor eight hours at room temperature. Thereafter the mixture was pouredinto fifty milliliters of ice water, neutralized by the addition ofdilute sodium hydroxide and the thus-obtained precipitate collected on afilter and dried to give6a-fiuoro-16a-methyl-l7a-hydroxy-1,4-pregnadiene-3,11,2-0-trione.

Following the procedure of Example 34, 6a,9a-difluoro-11B,17m-dihydroxy-16u-methyl 1,4 pregnadiene 3,20- dione was oxidized to6a,9a-difluoro-16a-methyl-l7ahydroxy-l ,4-pregnadiene-3 ,1 1,20-trione.

Similarly, 6a-fiuoro 16a methyl 17oz hydroxy-4- pregnene-3,ll,20-trioneis prepared from 6oc-fil101O-11B,17u-dihydroxy-16a-methyl-4-pregnene-3,20 dione and (Jon,9ot-difluoro-16a-methyl-l7a-hydroxy-4-pregnene 3,11,20- trione isprepared from 6a,9m-difluoro-l1B-17a-dihydroxy-16a-methyl-4-pregnene-3,ZO-dione. The corresponding 9onchloro compoundsare similarly prepared.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. 6u-flllOI'0-16a-mefl1yl steroid compounds of the formula:

wherein R is a member of the group consisting of hydrogen and the acylradical of a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive; R is a member of the group consisting of3-hydroxy and keto; and X is a member of the group consisting ofhydrogen, fluorine, and chlorine.

2. 6a-fluoro-11B,17a,21-trihydroxy 16a methyl 4- pregnene-3,20-dione.

3. 6u-fluoro-11,8,17a,21-trihydroXy 16a methyl 4- pregene-BJO-dione21-acylate wherein the acyl radical is that of a hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive.

4. 6m-fluoro-l1B,17a,21-trihydroxy 16a methyl 4- pregnene-3,20-dione21-acetate.

5. 6oz fluoro 16oz methyl l7rx,2l dihydroxy 4- pregnene-3,11,20-trione 2l-acetate.

6. 6oz fluoro 16a methyl 1711,21 dihydroxy 4- pregnene-3,1 1,20-trione.

7. 6Ct-fill0I'O-9at-hfll0 11B,17a,21 trihydroxy16amethyl-4-pregnene-3,ZO-dione 21-acylate wherein the acyl radical isthat of a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive, and wherein the halogen has an atomic weightfrom 19 to 36, inclusive.

8. 6a,9adifluoro-115,17a,21 trihydroxy 16a-methyl- 4-pregnene 3,20-dione21-acetate.

10. 16a-methyl steroid compounds of the formula:

wherein R is a member of the group consisting of hydrogen and the acylradical of a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, inclusive; R is a member of the group consisting of B-hydroxy and keto; and X is a member of the group consisting of hydrogen,fluorine, and chlorine.

11. 6oz-fiUOI0-l6a-II1Cthyl 170:,21 dihydroxy 1,4-pregnadiene-3,l1,20-trione 21-acetate.

12. 6a-fluoro-16a-methyl 170:,21 dihydroxy 1,4- pregnadiene-3,11,20-trione.

13. 6a-fiuoro-11B,17a,21-trihydroxy 16a methyl-1,4-pregnadiene-3,20-dione.

14. 6a-fluoro-11B,17a,21-trihydroXy 16m methyl-1,4-pregnadiene-3,20-dione 21-acylate wherein the acyl radical is that of ahydrocarbon carboxylic acid containing from one to twelve carbon atoms,inclusive.

15. 6a-fluor0-11B,17a,21-trihydroxy 16a methyl-1,4-pregnadiene-3,20-dione 21'acetate.

16. 6u-fluoro-9a-ha1o 11B,17a,21 trihydroxy 16::-methyl-l,4-pregnadiene-3,20-dione 21-acylate wherein the acyl radical isthat of a hydrocarbon carboxylic acid con taining from one to twelvecarbon atoms, inclusive, and wherein the halogen has an atomic weightfrom 19 to 36, inclusive.

17. 6a,9a-difluoro-11fi-17u,21-trihydroxy 16a-methyl-1,4-pregnadiene-3,ZO-dione 21-acetate.

18. 6a,9u-difiuoro-115,17a,21-trihydroxy 16a-methyl-1,4-pregnadiene-3,ZO-dione.

19. A compound selected from the group consisting of60:,2l-difluoro-l6a-methyl-17a-hydroxy 4 pregnene-Ia', ZO-clionesrepresented by the formula:

CHz-F $113 H30 811 R/\ om HsC l wherein X is selected from the groupconsisting of chlorine, fluorine and hydrogen atoms and R is selectedfrom the group consisting of B-hydroxy and keto, and the corresponding Acompound.

24. 6oz fluoro 11B,Not-dihydroxy-16u-methyl-4-pregnene-3,20-dione.

26. 6a,9a-diflu0fO11/3,l7ot dihydroxy 16u-methylpregnadiene-3,20-dione.

26. 6a,9adifluOIO-1lb,l7uz dihydroxy 16u-methy11,4-pregnadiene-3,20-dione.

27. 6a,9a-difiuoro-11,8,17a-dihydroxy-16a methyl 4- pregnene-3,20-dione.

28. A compound of the formula:

29. A compound of the group consisting of pregnenes of the formula:

CHzOR A fi EEm Ni and the 1,2-dehydro analogs thereof, wherein Xrepresents a member selected from the group consisting of ,B-hydroxyland keto, Y represents a member of the group consisting of hydrogen andhalogen, and R represents a member of the group consisting of hydrogenand lower-alkanoyl.

UNITED References Cited STATES PATENTS Spero et a1. 260-23955 Magerleinet a1. 260-23955 Spero et a1. 260-23955 Magerlein 'et a1. 260-397 .45Magerlein et a1. 260-397.45 Spero et a1. 260-39745 28 Spero et a1.260-397.45 Magerlein et a1. 260-397.45 Spero et a1. 260-39745 Spero eta1. 260-39745 Hogg et a1. 260-397.45

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.

1.6A-FLUORO-16A-METHYL STEROID COMPOUNDS OF THE FORMULA: